Microfluidic devices can offer a variety of advantages over macroscopic reactors, such as reduced reagent consumption, high surface-to-volume ratios, and improved control over mass and heat transfer. (See, K. Jahnisch, V. Hessel, H. Lowe, M. Baems, Angew. Chem. 2004, 116, 410-451; Angew. Chem. Int. Ed. Engl. 2004, 43, 406-446; P. Watts, S. J. Haswell, Chem. Soc. Rev. 2005, 34, 235-246; and G. Jas, A. Kirschning, Chem. Eur. J. 2003, 9, 5708-5723.) A microfluidic device can be integrated with a computer control system in order to perform complicated chemical and biological processes in an automated fashion.
Positron Emission Tomography (PET) is a molecular imaging technology that is increasingly used for detection of disease. PET imaging systems create images based on the distribution of positron-emitting isotopes in the tissue of a patient. The isotopes are typically administered to a patient by injection of probe molecules, which comprise a positron-emitting isotope, e.g. carbon-11, nitrogen-13, oxygen-15, or fluorine-18, attached to a molecule that is readily metabolized or localized in the body or that chemically binds to receptor sites within the body. The short half-lives of the positron emitters require that synthesis, analysis and purification of the probes are completed rapidly.
Single photon emission computed tomography (SPECT) is another nuclear medicine tomographic imaging technique using gamma rays emitted from positron probes. SPECT is able to provide true 3D information. In particular, gated SPECT (timed acquisition) of the heart can be used to obtain quantitative information about myocardial perfusion, thickness, and contractility of the myocardium during various parts of the cardiac cycle. Additionally, SPECT can be used for tumor imaging, infection (leukocyte) imaging, thyroid imaging or bone imaging. Isotopes commonly used in SPECT include technetium-99, iodine-123 and indium-111, which can be attached to a molecule that is readily metabolized or localized in the body or that chemically binds to receptor sites within the body.
Microfluidic devices have been designed and tested for radio-synthesis of radiometric probes. A microfluidic device for the multistep synthesis of a radiolabeled imaging probe has been disclosed in, for example Lee, C-C, et al., Science 2005 310:1793-1796; Gillies, J M et al., Appl Radiat Isot 2006 64(3):325-32 and 333-336; and Audrain Angew Chem Int Ed Engl 2007 46(11):1772-5. Those devices, as well as those disclosed in US 2007-0051412 and US 2004-0258615, are non-exclusive examples of the type synthetic devices that can be used with the systems disclosed herein.
In order for microfluidic devices to be used in clinical applications, the desired products need to be isolated in pure form and their quality has to be precisely analyzed and recorded. Radio-synthesis of probes in microfluidics devices generally yields very small amounts of product in a very small volume of typically aqueous solvent (1-50 μL, even 1-10 μL). It is difficult to analyze and purify these products by conventional methods, without losing the targeted product due to the small sample volumes compared to the volumes and surface area of the vessels and tubing the product encounters en route. When working with smaller sample volumes, product loss from routine handling and required transfers is more significant. Generally users either have accepted the purity and yield achieved by conventional HPLC or run multiple sequential purifications. However, conventional methods do not allow enough precision in the isolation of the desired peaks from HPLC; conventional methods also require manual handling which leads to product losses and introduces errors. Furthermore, the short half-life of many of the radiometric probes requires the development of any new analytical processes to be relatively fast and efficient, that is with relatively short overall processing cycles and high yields. The isolation/detection/collection systems of the present application are complementary to microfluidic radio-synthesis devices, which operate with small volumes.
The systems described in the present application provide small scale, integratable and self-contained units. These systems are substantially isolated from the outside environment, excepting reagent, buffer or sample ports, and are able to perform fluidic operations while maintaining precise control of the amounts of fluids to be delivered. The sealed nature and readily automatable systems also protect fluid operation performed in these devices from contaminating influences from the outside environment, such as chemical or biological contamination, including human error that is generally associated with manual operations, e.g. measurement errors, incorrect reagent additions, detection errors and the like.